Multiblock biodegradable hydrogels for drug delivery and tissue treatment

ABSTRACT

Gel-forming macromers including at least four polymeric blocks, at least two of which are hydrophobic and at least one of which is hydrophilic, and including a crosslinkable group are provided. The macromers can be covalently crosslinked to form a gel on a tissue surface in vivo. The gels formed from the macromers have a combination of properties including thermosensitivity and lipophilicity, and are useful in a variety of medical applications including drug delivery and tissue coating.

BACKGROUND OF THE INVENTION

[0001] This application is a continuation-in-part of U.S. Ser. No.60/001,723, filed Jul. 28, 1995.

[0002] The present invention is generally in the area of biodegradablepolymers for use in drug delivery and biomedical applications.

[0003] Biodegradable polymers have been developed for use in a varietyof surgical and drug delivery applications. The synthesis andbiodegradability of poly(lactic acid) was reported by Kulkarni et al.,Arch. Surg., 93:839 (1966). Biodegradable polyanhydrides andpolyorthoesters having labile backbone linkages have been developed.Domb et al., Macromolecules, 22:3200 (1989); and Heller et al.,“Biodegradable Polymers as Drug Delivery Systems,” Chasin, M. andLanger, R., Eds., Dekker, New York, 121-161 (1990), the disclosures ofwhich are incorporated herein. Polymers which degrade into naturallyoccurring materials, such as polyaminoacids, also have been developed.Polyesters of α-hydroxy acids, such as lactic acid or glycolic acid, arewidely used as biodegradable materials for applications ranging fromclosure devices, including sutures and staples, to drug deliverysystems. Holland et al., Controlled Release, 4:155-180, (1986); U.S.Pat. No. 4,741,337 to Smith et al.; and Spilizewski et al., J. Control.Rel., 2:197-203 (1985), the disclosures of which are incorporatedherein.

[0004] Degradable polymers containing water-soluble polymer elementshave been described. Degradable polymers have been formed bycopolymerization of lactide, glycolide, and ε-caprolactone with thepolyether, polyethylene glycol (“PEG”), to increase the hydrophilicityand degradation rate. Sawhney et al., J. Biomed. Mater. Res.24:1397-1411 (1990). U.S. Pat. No. 4,716,203 to Casey et at. describesthe synthesis of a block copolymer of PGA (poly(glycolic acid)) and PEG.U.S. Pat. No. 4,716,203 to Casey et al. describes the synthesis ofPGA—PEG diblock copolymers.

[0005] Polymers formed from crosslinkable monomers or prepolymers havebeen developed in the prior art. Crosslinked hyaluronic acid has beenused as a degradable swelling polymer for biomedical applications. U.S.Pat. Nos. 4,987,744 and 4,957,744 to Della Valle et al.; and Della Valleet al., Polym. Mater. Sci. Eng., 62:731-735 (1991).

[0006] U.S. Pat. No. 5,410,016 to Hubbell et al., the disclosure ofwhich in incorporated herein, discloses the in situ crosslinking ofbiodegradable, water-soluble macro-monomers, (“macromers”) to formbarrier coatings and matrices for delivery of biologically activeagents. Other polymers for drug delivery or other biomedicalapplications are described in U.S. Pat. No. 4,938,763 to Dunn, U.S. Pat.Nos. 5,160,745 and 4,818,542 to DeLuca, U.S. Pat. No. 5,219,564 toZalipsky, U.S. Pat. No. 4,826,945 to Cohn, and U.S. Pat. Nos. 5,078,994and 5,429,826 to Nair, the disclosures of which are incorporated hereinby reference. Methods for delivery of the polymers materials includesyringes (U.S. Pat. No. 4,938,763 to Dunn et al.) spray applicators (WO94/21324 by Rowe et al.) and catheter delivery systems (U.S. Pat. Nos.5,328,471; and 5,213,580 to Slepian). The synthesis of macromersIncluding a central chain of polyethylene glycol, with an oligomerichydroxyacid at each end and acrylic esters at the ends of the hydroxyacid oligomer also has been reported. Sawhney A. S. et al.,Macromolecules, 26: 581 (1993); and PCT WO 93/17669 by Hubbell J. A. etal., the disclosures of which are incorporated herein by reference.

[0007] Thermal volume changes in polymeric gels, such as esters andamides of polyacrylic acid, have been described. For example,poly(N-isopropyl acrylamide) based hydrogels, which are thermosensitivein aqueous systems, have been used for controlled drug delivery andother applications. U.S. Pat. No. 5,403,893 to Tanaka et al.; andHoffman A. S. et al., J. Controlled Release, 6:297 (1987), thedisclosures of which are incorporated herein. Poly(N-isopropylacrylamide), however, is non-degradable and is not suitable forapplications where biodegradable polymers are required.Non-biodegradable polymeric systems for drug delivery aredisadvantageous since they require removal after the drug-polymer deviceis implanted.

[0008] It is an object of the invention to provide improved polymersystems for use in drug delivery and other biomedical applications suchas surgical applications. It is an additional object of the invention toprovide polymer systems for use in controlled drug delivery which arecapable of releasing a biologically active agent in a predictable andcontrolled rate. It is a further object of the invention to providepolymers for use in controlled drug delivery which release the activeagent locally at a particular targeted site where it is needed. It isanother object of the invention to provide polymer systems for use indrug delivery which have properties including volume and drug releasewhich are variable with temperature or other parameters such as pH orion concentration.

SUMMARY OF THE INVENTION

[0009] Macromers are provided which are capable of gelling in an aqueoussolution. In one embodiment, the macromers include at least fourpolymeric blocks, at least one of which is hydrophilic and at least twoof which are hydrophobic, and include a crosslinkable group. The polymerblocks may be selected to provide macromers with different selectedproperties. The macromers can be covalently crosslinked to form a gel ona tissue surface in vivo. The gels formed from the macromers have acombination of properties including thermosensitivity and lipophilicity,and are useful in a variety of medical applications including drugdelivery and tissue coating.

BRIEF DESCRIPTION OF THE FIGURES

[0010]FIG. 1 is a scheme showing the different gel states and propertiesof one embodiment of a thermoresponsive biodegradable macromer formedfrom a polypropylene oxide-polyethylene oxide block copolymer.

[0011]FIG. 2 is a graph of temperature-dependent changes in gel volumeof gels formed by photopolymerization of an acrylated polypropyleneoxide-polyethylene oxide block copolymer containing a biodegradableregion.

[0012]FIG. 3 is a graph showing the effects of temperature on dextranrelease from a gel formed by photopolymerization of an acrylatedpolypropylene oxide-polyethylene oxide block copolymer.

[0013]FIG. 4 is a graph illustrating the variation in the speed ofphotocrosslinking of acrylated polypropylene oxide-polyethylene oxideblock copolymers having incorporated therein different biodegradableregions.

[0014]FIG. 5 is a graph showing the in vitro profiles of degradationrate of gels formed by photocrosslinking of acrylated polypropyleneoxide-polyethylene oxide block copolymers having incorporated thereindifferent biodegradable regions.

[0015]FIG. 6 is a graph illustrating the biocompatibility of gels formedby photocrosslinking acrylated polypropylene oxide-polyethylene oxideblock copolymers having incorporated therein different biodegradableregions.

[0016]FIG. 7 shows graphs illustrating release of fluorescent dextranfrom gels formed by photocrosslinking acrylated polypropyleneoxide-polyethylene oxide block copolymers having incorporated thereinbiodegradable linkers.

[0017]FIG. 8 shows graphs of transition temperatures of gels formed frommacromers containing biodegradable linkers.

[0018]FIG. 9 illustrates the chemical structures of biodegradablecrosslinkable macromers consisting of acrylated poly(propyleneoxide)-poly(ethylene oxide) block copolymers having incorporated thereina biodegradable linker.

[0019]FIG. 10 is a graph of absorbance of a hydrophobic dye vs. log(weight %) of solutions of biodegradable macromers having a hydrophobicregion incorporated therein.

[0020]FIG. 11 is a schematic illustration of a cell membrane includinghydrophobic bilayer with a macromer including a hydrophobic taildiffused into the bilayer.

[0021]FIG. 12 is a schematic illustration of nanospheres or microsphereswhich can be formed by aggregation and subsequent polymerization ofhydrophilic macromers.

[0022]FIG. 13 is a graph which shows the rate of release of a small drugfrom gels formed from hydrophobic macromers.

[0023]FIGS. 14 and 15 are graphs showing diffusivity of a sparinglywater soluble drug through a hydrophobic hydrogel.

[0024]FIG. 16 is a graph showing the release of tetracycline from ahydrogel formed from monomers including a biodegradable region.

DETAILED DESCRIPTION OF THE INVENTION

[0025] Macromers are provided which are crosslinkable to form hydrogelswhich are useful as matrices for controlled drug delivery. In apreferred embodiment, biodegradable macromers are provided in apharmaceutically acceptable carrier, and are capable of crosslinking,covalently or non-covalently, to form hydrogels which arethermoresponsive. A biologically active agent may be incorporated withinthe macromer solution or in the resulting hydrogel after crosslinking.The hydrogels have properties, such as volume and drug release rate,which are dependent upon temperature. The hydrogels may be formed insitu, for example, at a tissue site, and may be used for for controlleddelivery of bioactive substances and as tissue coatings. The macromersused to form the hydrogels may be fabricated with domains havingspecific properties including selected hydrophobicity, hydrophilicity,thermosensitivity or biodegradability, and combinations thereof.

[0026] Macromers

[0027] The macro-monomers (“macromers”) which are ionically orcovalently crosslinkable to form hydrogels preferably consist of a blockcopolymer. The macromers can be quickly polymerized from aqueoussolutions. The macromers are advantageously capable of thermoreversiblegelation behavior, and preferably may be polymerized in a solution stateor in a gel state. The macromers are defined as including a hydrophilicblock capable of absorbing water, and at least one block, distinct fromthe hydrophilic block, which is sufficiently hydrophobic to precipitatefrom, or otherwise change phase while within, an aqueous solution,consisting of water, preferably containing salts, buffers, drugs orpolymerizing reagents, at temperatures within or near thephysiologically compatible range, for example 0 to 65° C. Thehydrophilic block optionally may be an amphiphilic block. The macromermay include more than one of the same or different hydrophilic orhydrophobic region. Preferably, the macromers include at least threeblocks, or more preferably four blocks.

[0028] The block copolymers may be linear (AB, ABA, ABABA or ABCBAtype), star (AnB or BAnC, where B is at least n-valent, and n is 3 to 6)or branched (multiple A's depending from one B). In these formulae,either A or B may be the hydrophilic block, and the other theamphipathic or hydrophilic block, and the additional block C may beeither.

[0029] In another embodiment, the macromer includes at least fourcovalently-linked polymeric blocks, wherein: at least one, or in anotherembodiment, at least two blocks are hydrophilic, and the hydrophilicblocks individually have a water solubility of at least 1 gram/liter; atleast two blocks are sufficiently hydrophobic to aggregate to formmicelles in an aqueous continuous phase; and the macromer furtherincludes at least one crosslinkable group. The crosslinkable groupsoptionally may be separated by at least one degradable linkage capableof degrading under physiological conditions. In one embodiment, at leastone hydrophobic block may be separated from any reactive group by atleast one hydrophilic block.

[0030] The macromer further may include five total blocks having thesame or different properties such as thermal sensitivity, hydrophilicityor hydrophobicity. Each block also may have a combination of properties.For example, a block may be hydrophilic and also thermosensitive.Additionally, the multiblock macromer may include chemically distinctblocks or may incorporate more than one of the same identical block. Themacromer is fabricated with a structure and with properties suitable fordifferent applications. For example the macromer may include a centralblock of dimer fatty acid which includes central hydrocarbon chain ofabout 30 carbon atoms and two terminal carboxy groups which areesterified with a thermosensitive poloxamer, such as Pluronic L1050.This central molecule further is polylactated at each hydroxy terminus,and end capped with acryloyl chloride. An another embodiment is apoloxamer including polyhydroxy groups polymerized on each end, andwherein the molecule is end capped at each end with a reactive groupsuch as an acrylate or a secondary isocyanate.

[0031] The configuration of the macromers may be preselected dependingon the use of the macromer. The macromers may include at least twohydrophobic blocks, separated by a hydrophilic block. The macromers alsomay be fabricated with a crosslinkable group which is separated by adegradable group from any other crosslinkable group. One preferredembodiment is wherein the dry macromer absorbs at least about 10% inweight of water. The molecular weight of the macromer preferably is atleast 1000 Daltons, or optionally is at least 2000 Daltons, or in analternative embodiment, at least 4000 Daltons.

[0032] In a preferred embodiment, the macromer includes at least onethermally sensitive region, and an aqueous solution of the macromer iscapable of gelling either ionically and/or by covalent crosslinking toproduce a hydrogel with a temperature dependent volume. This permits therate of release of a drug incorporated in the hydrogel to changedepending upon the volume of the hydrogel. Useful macromers are thosewhich are, for example, capable of thermoreversible gelation of anaqueous solution of the macromer at a concentration of at least 2% byweight, and wherein the gelation temperature is between about 0° C. andabout 65° C. The macromer also may have a phase transition temperaturein the range of 0 to 100° C., and wherein the transition temperature isaffected by the ionic composition of an aqueous solution of the macromeror the concentration of macromer in the aqueous solution.

[0033] The macromers may be formed by modification of materials andmethods described in the prior art. Macromers including a central chainof polyethylene glycol, with oligomeric hydroxy acid at each end andacrylic esters at the ends of the hydroxy acid oligomer are described inSawhney A. S. et al., Macromzolecules, 26: 581 (1993); and PCT WO93/17669 by Hubbell J. A. et al., the disclosures of which areincorporated herein by reference. U.S. Pat. No. 5,410,016 to Hubbell etal., the disclosure of which is incorporated herein by reference,discloses that biodegradable, water-soluble macromers can be crosslinkedin situ to form barrier coatings and depots or matrices for delivery ofbiologically active agents such as therapeutic drugs. In addition to thematerials and methods described in U.S. Pat. No. 5,410,016, materialsand methods described by Dunn (U.S. Pat. No. 4,938,763), DeLuca (U.S.Pat. Nos. 5,160,745; and 4,818,542), Zalipsky (U.S. Pat. No. 5,219,564),Cohn (U.S. Pat. No. 4,826,945), Nair (U.S. Pat. Nos. 5,078,994; and5,429,826), the disclosures of which are incorporated herein byreference, are useful to form the macromers described herein.

[0034] For example, the macromer may include a poloxamer backboneextended with hydrophobic materials, such as oligolactate moieties,which serve as the biodegradable segment of the molecule, wherein thePEO—PPO—PEO-lactate copolymer is terminated by acrylate moieties. Thematerials can be combined with, then delivered and photopolymerized insitu, onto target organs to conform to a specific shape.

[0035] The macromers and hydrogels formed therefrom preferably arebiocompatible, preferably not causing or enhancing a biological reactionwhen implanted or otherwise administered within a mammal. The macromers,and any breakdown products of the hydrogels or macromers, preferably arenot significantly toxic to living cells, or to organisms. The hydrogelsalso may have liquid crystalline properties for example at highconcentration, which are useful in controlling the rate of drugdelivery. Ionic properties can be provided in the backbone of themacromers, conferring the further property of control of delivery and/orphysical state by control of the ionic environment, including pH, of themacromer or gel. In one embodiment, the critical ion composition is thehydrogen ion concentration. For example, when a poloxamine, such as aTetronic surfactant, is used as the core of the macromer, then theresulting macromer has the ionic groups (amines) in the core, and themacromers' ability to gel upon changes in temperature is affected by thepH of the solution.

[0036] Thermosensitive Regions

[0037] The macromers may be provided with one or more regions which haveproperties which are thermoresponsive. As used herein,thermoresponsiveness is defined as including properties of a hydrogel,such as volume, transition from a liquid to a gel, and permeability tobiologically active agents, which are dependent upon (he temperature ofthe hydrogel In one embodiment, the macromers are capable of reversiblegelation which is controlled by temperature. The reversible gel furtheroptionally may be crosslinked in situ into an irreversibly andcovalently crosslinked gel. This permits the macromer to be appliedreliably in surgical applications on a specific area of tissue withoutrunning off or being washed off by body fluids prior to gelation orcrosslinking.

[0038] In one preferred embodiment, the macromers are capable of gellingthermoreversibly, for example, due to the content of poloxamer regions.Since gelling is thermoreversible, the gel will dissipate on cooling.The macromers may further include crosslinkable groups which permit thegel to be further covalently crosslinked for example byphotopolymerization. After crosslinking, the gels are irreversiblycrosslinked. However, they retain other significant thermoresponsiveproperties, such as changes in volume and in permeability.

[0039] By appropriate choice of macromer composition, hydrogels can becreated in situ which have thermosensitive properties, including volumechanges and drug release which are dependent upon temperature, which canbe used to control drug delivery from the hydrogel. Control of drugdelivery can be further controlled by adjustment of properties such ashydrophobicity of amphiphilic or other regions in the gel. Change involume of the hydrogel may readily be measured by examination ofmacroscopic unrestrained samples during temperature excursions. Changesin excess of 100% in volume may be obtained with hydrogels formed fromthe macromers, such as an acrylate-capped polyglycolide-derivatizedpoloxamer of about 30% PPO (polypropylene oxide) content, the expansionoccurring gradually on change of the temperature from about 0° C. tobody temperature (37° C.). Changes of more than 5% in any lineardimension may be effective in altering the release rate of amacromolecular drug.

[0040] The macromers preferably include thermogelling macromers, such as“poloxamers”, i.e., poly(ethylene oxide)-poly(propyleneoxide)-poly(ethylene oxide) (“PEO—PPO—PEO”), block copolymers. Aqueouspolymeric solutions of poloxamers undergo microphase transitions at anupper critical solution temperature, causing a characteristic gelformation. This transition is dependent on concentration and compositionof the block copolymer. Alexandridis et al., Macromolecules, 27:2414(1994). The segmental polyether portion of the molecule gives watersolubility and thermosensitivity. The material also advantageously havebeen demonstrated to be biocompatible.

[0041] For example, the macromer may include a poloxamer backboneextended with hydrophobic materials, such as oligolactate moieties,which serve as the biodegradable segment of the molecule, wherein thePEO—PPO—PEO-lactate copolymer is terminated by acrylate moieties. Thematerials can be combined with a bioactive agent, then delivered andphotopolymerized in situ. In addition to poloxamer cores, meroxapols,such as “reversed Pluronics” (PPO—PEO—PPO copolymers) and poloxamines,such as Tetronic™ surfactants, may be used.

[0042] Other polymer blocks which may be provided in the monomer whichare capable of temperature dependent volume changes include watersoluble blocks such as polyvinyl alcohol, polyvinyl-pyrrolidone,polyacrylic acids, esters and amides, soluble celluloses, peptides andproteins, dextrans and other polysaccharides. Additionally, polymerblocks with an upper critical point may be used, such as otherpolyalkylene oxides, such as mixed polyalkylene oxides and esters,derivatized celluloses, such as hydroxypropylmethyl cellulose, andnatural gums such as konjac glucomannan.

[0043] In another embodiment, the macromer is defined as having anoptically anisotropic phase at a concentration at or below the maximalsolubility of the macromer in an aqueous solution, at a temperaturebetween about 0 and 65° C.

[0044] Crosslinkable Groups.

[0045] The macromers preferably include crosslinkable groups which arecapable of forming covalent bonds with other compounds while in aqueoussolution, which permit crosslinking of the macromers to form a gel,either after, or independently from thermally dependent gellation of themacromer Chemically or ionically crosslinkable groups known in the artmay be provided in the macromers. The crosslinkable groups in onepreferred embodiment are polymerizable by photoinitiation by freeradical generation, most preferably in the visible or long wavelengthultraviolet radiation. The preferred crosslinkable groups areunsaturated groups including vinyl groups, allyl groups, cinnamates,acrylates, diacrylates, oligoacrylates, methacrylates, dimethacrylates,oligomethoacrylates, or other biologically acceptable photopolymerizablegroups.

[0046] Other polymerization chemistries which may be used include, forexample, reaction of amines or alcohols with isocyanate orisothiocyanate, or of amines or thiols with aldehydes, epoxides,oxiranes, or cyclic imines; where either the amine or thiol, or theother reactant, or both, may be covalently attached to a macromer.Mixtures of covalent polymerization systems are also contemplated.Sulfonic acid or carboxylic acid groups may be used.

[0047] Preferably, at least a portion of the macromers will have morethan one crosslinkable reactive group, to permit formation of a coherenthydrogel after crosslinking of the macromers. Up to 100% of themacromers may have more than one reactive group. Typically, in asynthesis, the percentage will be on the order of 50 to 90%, forexample, 75 to 80%. The percentage may be reduced by addition of smallco-monomers containing only one active group. A lower limit forcrosslinker concentration will depend on the properties of theparticular macromer and the total macromer concentration, but will be atleast about 3% of the total molar concentration of reactive groups. Morepreferably, the crosslinker concentration will be at least 10%, withhigher concentrations, such as 50% to 90%, being optimal for maximumretardation of many drugs. Optionally, at least part of the crosslinkingfunction may be provided by a low-molecular weight crosslinker. When thedrug to be delivered is a macromolecule, higher ranges of polyvalentmacromers (i.e., having more than one reactive group) are preferred. Ifthe gel is to be biodegradable, as is preferred in most applications,then the crosslinking reactive groups should be separated from eachother by biodegradable links. Any linkage known to be biodegradableunder in vivo conditions may be suitable, such as a degradable polymerblock. The use of ethylenically unsaturated groups, crosslinked by freeradical polymerization with chemical and/or photoactive initiators, ispreferred as the crosslinkable group.

[0048] The macromer may also include an ionically charged moietycovalently attached to the macromer, which optionally permits gellationor crosslinking of the macromer.

[0049] Hydrophobic Regions

[0050] The macromers further may include hydrophobic domains. Thehydrophobicity of the gel may be modified to alter drug delivery orthree dimensional configuration of the gel. Amphiphilic regions may beprovided in the macromers which in aqueous solution tend to aggregate toform micellar domain, with the hydrophobic regions oriented in theinterior of these domains (the “core”), while the hydrophilic domainsorient on the exterior (“the corona”). These microscopic “cores” canentrap hydrophobic drugs, thus providing microreservoirs for sustaineddrug release. Kataoka K., et al., J. Controlled Release, 24:119 (1993).

[0051] The fundamental parameter of this supramolecular assemblage ofamphiphilic polymers in aqueous solution is the Critical MicellarConcentration (CMC), which can be defined as the lowest concentration atwhich the dissolved macromolecules begin to self-assemble. By selectionof the hydrophilic and other domains, drug delivery can be controlledand enhanced.

[0052] In one embodiment, the macromers are provided with at least onehydrophobic zone, and can form micelles including a region in whichhydrophobic materials will tend to bind and thus tend to reduce escapeof the drug from the formed gel. The hydrophobic zone may be enhanced byaddition of materials, including polymers, which do not contribute tothe formation of a gel network but which segregate into such zones toenhance their properties, such as a fatty acid, hydrocarbon, lipid, or asterol.

[0053] The ability of the macromonomers in one embodiment to formmicellar hydrophobic centers not only allows the controlled dissolutionof hydrophobic bioactive compounds but also permits the hydrogel toselectively “expand” and “contract” around a transition temperature.This provides an “on-off” thermocontrol switch which permits thethermally sensitive delivery of drugs.

[0054] The cell membrane is composed of a bilayer with the inner regionbeing hydrophobic. This bilayer is believed to have a fluid and dynamicstructure, i.e., hydrophobic molecules can move around in this structureA hydrophobic tail incorporated in a macromer can diffuse into thislipid bilayer and result in the rest of the macromonomer (thus, thehydrogel) to better adhere to the tissue surface (see FIG. 11). Thechoice of molecular group to be used as hydrophobic tail is guided bythe fatty acid composition of the bilayer to assure minimum perturbationof the bilayer structure. Examples of suitable groups are fatty acids,diacylglycerols; molecules from membranes such as phosphatidylserine,and polycyclic hydrocarbons and derivatives, such as cholesterol, cholicacid, steroids and the like. Preferred hydrophobic groups for thispurpose are normal constituents of the human body. These molecules willbe used at a low concentration relative to native molecules in themembrane.

[0055] Use of macromers carrying one or more hydrophobic groups canimprove the adherence of a hydrogel to a biological material byanchoring a segment of the hydrogel in the lipid bilayer. This anchoringwill cause minimal perturbation to the underlying tissue because theinsertion of the fatty acid terminal of the macromer into the lipidmembrane involves purely physical interaction. The macromer may beapplied by using a prewash of the surface with these molecules, ineffect “preparing” the surface for coupling and/or an in situphotopolymerization of a mixture of these lipid-penetrating moleculeswith the crosslinkable macromers.

[0056] The hydrophobic region may include oligomers of hydroxy acidssuch as lactic acid or glycolic acid, or oligomers of caprolactone,amino acids, anhydrides, orthoesters, phosphazenes, phosphates,polyhydroxy acids or copolymers of these subunits. Additionally thehydrophobic region may be formed of poly(propylene oxide), poly(butyleneoxide), or a hydrophobic non-block mixed poly(alkylene oxide) orcopolymers thereof. Biodegradable hydrophobic polyanhydrides aredisclosed in, for example, U.S. Pat. Nos. 4,757,128, 4,857,311,4,888,176, and 4,789,724, the disclosure of which is incorporated byreference herein. Poly L-lactide, or poly D,L-lactide for example may beused. In another embodiment the hydrophobic region may be a polyesterwhich is a copolymer of poly(lactic-co-glycolic) acid (PLGA).

[0057] The macromer also may be provided as a mixture including ahydrophobic material non-covalently associated with the macromer,wherein the hydrophobic material is, for example, a hydrocarbon, alipid, a fatty acid, or a sterol.

[0058] Hydrophilic Regions.

[0059] Water soluble hydrophilic oligomers available in the art may beincorporated into the biodegradable macromers. The hydrophilic regioncan be for example, polymer blocks of poly(ethylene glycol),poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone),poly(ethyloxazoline), or polysaccharides or carbohydrates such ashyaluronic acid, dextran, heparan sulfate, chondroitin sulfate, heparin,or alginate, or proteins such as gelatin, collagen, albumin, ovalbumin,or polyamino acids.

[0060] Biodegradable Regions

[0061] Biodegradable molecules or polymers thereof available in the artmay be incorporated into the macromers. The biodegradable region ispreferably hydrolyzable under in vivo conditions. In some embodiments,the different properties, such as biodegradability and hydrophobicity orhydrophilicity, may be present within the same region of the macromer.

[0062] Useful hydrolyzable groups include polymers and oligomers ofglycolide, lactide, epsilon-caprolactone, other hydroxy acids, and otherbiologically degradable polymers that yield materials that are non-toxicor present as normal metabolites in the body. Preferredpoly(alpha-hydroxy acids) are poly(glycolic acid), poly(DL-lactic acid)and poly(Ilactic acid). Other useful materials include poly(aminoacids), polycarbonates, poly(anhydrides), poly(orthoesters),poly(phosphazines) and poly(phosphoesters) Polylactones such aspoly(epsilon-caprolactone), poly(delta-caprolactone),poly(delta-valerolactone) and poly(gamma-butyrolactone), for example,are also useful. The biodegradable regions may have a degree ofpolymerization ranging from one up to values that would yield a productthat was not substantially water soluble. Thus, monomeric, dimeric,trimeric, oligomeric, and polymeric regions may be used.

[0063] Biodegradable regions can be constructed from polymers ormonomers using linkages susceptible to biodegradation, such as ester,peptide, anhydride, orthoester, phosphazine and phosphoester bonds. Thetime required for a polymer to degrade can be tailored by selectingappropriate monomers. Differences in crystallinity also alterdegradation rates. For relatively hydrophobic polymers, actual mass lossonly begins when the oligomeric fragments are small enough to be watersoluble. Thus, initial polymer molecular weight influences thedegradation rate.

[0064] Therapeutic Applications

[0065] Biodegradable, temperature responsive hydrogels can be formed insitu and may be use in a variety of therapeutic applications includingsurgical applications In one embodiment the gels can be appliedtopically to the skin to treat a variety of conditions such as abrasion,keratoses, inflammatory dermatoses, injury resulting from a surgicalprocedure, and disturbed keratinization. The hydrogels may includetherapeutic agents such as antibiotics, or antifungals for the localizedtreatment of different skin conditions.

[0066] Macromers which are liquid at room temperature and gel at bodytemperature, such as macromers including a Pluronic™ poloxamer, may beused in treatment of burns and other external injuries. The hydrogelsare useful in bum applications, since the hydrogel layer formed on theskin provides local or transdermal delivery of drug to the burn site;maintains high moisture levels on severely burned sites, thusdiminishing dehydration; adheres strongly to the damaged tissue, and iselastic, thus minimizing delamination and “peeling” of the hydrogeldressing; and absorbs exudate from the wound. Hydrogels may be selectedwhich dissolve into components which are absorbable and non-toxic, whichpromote healing, and gel spontaneously and quickly on the burn site,prior to optional further crosslinking.

[0067] The macromers also may be applied to biological tissue, or on thesurface of a medical device, to form hydrogels in a variety of surgicalapplications for the treatment of tissue or organs. The gel also may beapplied between two surfaces, such as tissue surfaces, to adhere thesurfaces. The hydrogels may be applied to tissue such as vasculartissue, for example for the treatment of restenosis of the arteries orin angioplasty procedures. A biologically active material may beprovided in the gel optionally in the form of particles, microparticles,pro-drug conjugates, or liposomes. The macromers may be designed suchthat the crosslinked gel changes in permneability in response to achange in temperature, ionic concentration or a change in pH, therebyaltering the rate of drug release from the hydrogel.

[0068] Drug Delivery

[0069] The macromers may be crosslinked reversibly or irreversibly toform gels for controlled drug delivery applications. The composition andproperties of the macromers can be selected and fabricated to producehydrogels with desired drug delivery properties. The drug may beprovided in the macromer solution prior to or after administration, andeither before or after gel formation, depending on the macromercomposition.

[0070] For example, the gels can be designed to have a selected rate ofdrug release, such as first order or zero order drug release kinetics.For specific drugs, such as peptides, the composition of the gel may bedesigned to result in pulsatile or mixed wave release characteristics inorder to obtain maximum drug efficacy and to minimize side effects andtolerance development. Bae et at., Pharnaceutical Research, 8: 531(1991).

[0071] The drug release profiles can be selected by the use of macromersand gels formed therefrom that respond to specific external stimuli suchas ultrasound, temperature, pH or electric current. For example, theextent of swelling and size of these hydrogels can be modulated. Changesinduced in the swelling directly correlate to the rate of release of theincorporated drugs. Through this, a particular release profile may beobtained. The hydrogels are preferably biodegradable so that removal isnot required after administration or implantation.

[0072] The gels permit controlled drug delivery and release of abiologically active agent in a predictable and controlled manner locallyat the targeted site where it is needed, when the tissue to be treatedis localized. In other embodiments, the gels also can be used forsystemic delivery.

[0073] A variety of therapeutic agents can be delivered using thehydrogels. Examples include synthetic inorganic and organic compounds,proteins and peptides, polysaccharides and other sugars, lipids,gangliosides, and nucleic acid sequences having therapeutic,prophylactic or diagnostic activities. Nucleic acid sequences includegenes, antisense molecules which bind to complementary DNA to inhibittraiscription, and ribozymes. The agents to be incorporated can have avariety of biological activities, such as vasoactive agents, neuroactiveagents, hormones, anticoagulants, imnmunomodulating agents, cytotoxicagents, antibiotics, antivirals, antisense, antigens, and antibodies.Proteins including antibodies or antigens can also be delivered.Proteins are defined as consisting of 100 amino acid residues or more;peptides are less than 100 amino acid residues. Unless otherwise stated,the term protein refers to both proteins and peptides. Examples includeinsulin and other hormones.

[0074] Specific materials include antibiotics, antivirals,antiinflamrnatories, both steroidal and non-steroidal, antineoplastics,antispasmodics including channel blockers, modulators ofcell-extracellular matrix interactions including cell growth inhibitorsand anti-adhesion molecules, enzymes and enzyme inhibitors,anticoagulants and/or antithrombotic agents, growth factors, DNA, RNA,inhibitors of DNA, RNA or protein synthesis, compounds modulating cellmigration, proliferation and/or growth, vasodilating agents, and otherdrugs commonly used for the treatment of injury to tissue. Specificexamples of these compounds include angiotensin converting enzymeinhibitors, prostacyclin, heparin, salicylates, nitrates, calciumchannel blocking drugs, streptokinase, urokinase, tissue plasminogenactivator (TPA) and anisoylated plasminogen activator (TPA) andanisoylated plasminogen-streptokinase activator complex (APSAC),colchicine and alkylating agents, and aptomers Specific examples ofmodulators of cell interactions include interleukins, platelet derivedgrowth factor, acidic and basic fibroblast growth factor (FGF),transformation growth factor a (TGF B), epidermal growth factor (EGF),insulin-like growth factor, and antibodies thereto Specific examples ofnucleic acids include genes and cDNAs encoding proteins, expressionvectors, antisense and other oligonucleotides such as ribozymes whichcan be used to regulate or prevent gene expression. Specific examples ofother bioactive agents include modified extracellular matrix componentsor their receptors, and lipid and cholesterol sequestrants.

[0075] Examples of proteins further include cytokines such asinterferons and interleukins, poetins, and colony-stimulating factors.Carbohydrates include Sialyl Lewis^(x) which has been shown to bind toreceptors for selectins to inhibit inflammation. A “Deliverable growthfactor equivalent” (abbreviated DGFE), a growth factor for a cell ortissue, may be used, which is broadly construed as including growthfactors, cytokines, interferons, interleukins, proteins,colony-stimulating factors, gibberellins, auxins, and vitamins; furtherincluding peptide fragments or other active fragments of the above; andfurther including vectors, i.e., nucleic acid constructs capable ofsynthesizing such factors in the target cells, whether by transformationor transient expression; and further including effectors which stimulateor depress the synthesis of such factors in the tissue, includingnatural signal molecules, antisense and triplex nucleic acids, and thelike. Exemplary DGFE's are vascular endothelial growth factor (VEGF),endothelial cell growth factor (ECGF), basic fibroblast growth factor(bFGF), bone morphogenetic protein (BMP), and platelet derived growthfactor (PDGF), and DNA's encoding for them. Exemplary clot dissolvingagents are tissue plasminogen activator, streptokinase, urokinase andheparin.

[0076] Drugs having antioxidant activity (i.e., destroying or preventingformation of active oxygen) may be provided in the hydrogel, which areuseful, for example, in the prevention of adhesions. Examples includesuperoxide dismutase, or other protein drugs include catalases,peroxidases and general oxidases or oxidative enzymes such as cytochromeP450, glutathione peroxidase, and other native or denaturedhemoproteins.

[0077] Mammalian stress response proteins or heat shock proteins, suchas heat shock protein 70 (hsp 70) and hsp 90, or those stimuli which actto inhibit or reduce stress response proteins or heat shock proteinexpression, for example, flavonoids, may be provided in the hydrogel.

[0078] The macromers may be provided in pharmaceutical acceptablecarriers known to those skilled in the art, such as saline or phosphatebuffered saline. For example, suitable carriers for parenteraladministration may be used.

[0079] Administration of Macromers

[0080] Modern surgical procedures which provide access to a variety oforgans using minimally invasive surgical devices may be used to applythe macromers. Using techniques such as laparoscopy/endoscopy, it ispossible to deposit a macromonomer solution at a localized site andsubsequently polymerize it inside the body. This method of “on-site”polymerization offers unique advantages such as conformity to specificorgans and adherence to underlying tissue. Hill-West J. L. et al.,Obstetrics & Gynecology, 83:59 (1994). Catheter delivery systemsavailable in the art also may be used as described, for example, in U.S.Pat. Nos. 5,328,471 and 5,213,580 to Slepian. The macromer also mayapplied during surgery conducted through the cannula of a trocar.

[0081] Formation of Microspheres

[0082] In one embodiment, the biodegrabable macromers are crosslinked,either reversibly or nonreversibly to form microspheres. As used herein,the term “microspheres” includes includes particles having a uniformspherical shape or an irregular shape, and microcapsules (having a coreand an outer layer of polymer) which generally have a diameter from thenanometer range up to about 5 mm. In a preferred embodiment, themicrospheres are dispersed in biocompatible, biodegradable hydrogelmatrices. The microspheres are useful for controlled release andtargeted delivery of drugs within the body.

[0083] The microspheres are formed in one embodiment by aggregation andsubsequent polymerization of portions of the macromers which are similarin charge properties such as hydrophilicity. This results in a matrixwhich consists of spontaneously-assembled “nodes”, which may becrosslinked covalently, and may be further covalently linked tohydrophilic bridges of the macromers to form a hydrogel.

[0084] When the macromer is amphiphilic and includes hydrophobic andhydrophilic domains, in an aqueous environment, at or above a certainconcentration, the molecules to arrange themselves into organizedstructures called micelles, at the critical micellar concentration(CMC)These micelles can be of different shapes and sizes, though aregenerally spherical or elliptical shape. When the solution is water, thehydrophobic portions are at the center of the micelle while thehydrophilic tails orient themselves toward water. The interior core of atypical surfactant has a size from 10-30 Angstroms. Pluronic™ poloxamerbased biodegradable macromers, as described in Examplel, undergomicellization in an aqueous environment with CMC values ranging between0 and 5% (w/v). After photopolymerization and gelation, this micellarstructure is preserved in the crosslinked gel. On a microscopic level,the gel contains micelles which are interconnected by covalent bonds toform the gel. These micellar domains or microspheres can be used for thecontrolled or sustained release of drugs. A schematic representation ofsuch a material is shown in FIG. 12. Controlled, pseudo-zero orderrelease of small compounds such as chlorohexidine is possible from suchhydrogels.

[0085] The hydrogel thus is formed in one embodiment by providing asolution of macromer in aqueous solution (with or without drug);“freezing” the micellar structure of the macromer by a chemicalcrosslinking via a chemical reaction; adding the drug to the crosslinkedmacromer if it has not been already added; and using the resultantdispersed composite, containing microspheres consisting ofdrug-attracting micellar cores, for drug delivery.

[0086] In addition to photopolymerization, crosslinking can beimplemented by, for example, isocyanate-amine chemistry, or hydroxy- oraldehyde-amine chemistry, to freeze micellar structure. For example,isocyanate terminated poloxamer lactate diol can react in water to formcrosslinked polyurethane based networks. This is an advantageous methodof forming a drug delivery device for local or systemic delivery,because the formation of the delivery-controlling micropheres and themicrosphere-confining gel is accomplished simultaneously, and may beaccomplished at the site of delivery in a few seconds byphotopolymerization.

[0087] In one embodiment the macromer includes PEO segments, andhydrophobic “ends” containing reactive groups, and the micellar domainsare hydrophobic and are interlinked by the PEG segments to form ahydrogel. Reversible gelling microsphere forming macromers also may bemade from Pluronics™ (PEG—PPO—PEG), lactylated and acrylate-capped,which are gelled and reacted in a non-aqueous phase. A hydrophilic drugthen may be added (while in the hydrophobic solvent) which partitions tothe hydrophilic core. Because the micelles have been cross-linked in thehydrophobic environment, they will not be able to revert to theconformation which they would normally assume in a hydrophilicenvironment. The trapped hydrophilic drug molecules then need to diffusethrough a relatively hydrophobic region to escape from the nanoparticle.This permits flexibility in the formation of microspheres.

[0088] They may be hydrophilic or hydrophobic depending on the solventin which they are polymerized, and on the composition of the macromersInother embodiments, physical or chemical crosslinking to form hydrogels(or organogels) can occur in zones other than those responsible for theprimary sustained release characteristics of the matrix. For example,“single-ended” materials could have alternative reaction sites on thenon-micellar ends, which could subsequently reacted to form a gel. Sincematrix-controlled drug delivery is a function of both diffusion from themicelles and of matrix degradation, manipulation of the macromolecularbackbone can also control matrix degradation. This can occur throughstabilization of hydrolytic groups by their chemical and physicalenvironment (for example, macromers based on reverse Pluronic™ gels aremore stable than normal Pluronic™ gels, in aqueous solution). It ispossible that the increased hydrophobicity of the environment of thelactide ester bonds, due to the adjacent block being PPO rather thanPEO, inhibits hydrolysis of the bond.

[0089] Alternatively, and particularly in gel-forming compositions, thecross-linking reactive groups or biodegradable groups may be in thehydrophilic portions of the macromers, so that the hydrophobic domainswould not be locally crosslinked in the hydrophobic regions, while themicelles would still be stabilized by the crosslinking of the material,and particular hydrophobic sections of macromers would be stericallyrestricted to one or only a few different micelles. In either of thesecases, the hydrophobic zones are not rigidly crosslinked, but areconnected to crosslinks via the hydrophilic blocks, which may be veryflexible. The hydrophobic blocks thus can associate above or below acritical temperature, and dissociate on change in temperature. Thisallows, for example, both thermosensitive gelation and thermosensitivevariation in drug diffusion rate.

[0090] The hydrogels may be designed to be biodegradable byincorporation of a group such as a lactide, glycolide or otherself-degrading linkage. Alternatively, this is not necessary whennon-gelled nanospheres are formed, since these are small enough to beremoved by phagocytosis. Control of the rates of delivery of both smalland large molecules can be obtained by control of the hydrophobicity ofthe associating hydrophobic domains of amphipathic hydrogels.

[0091] The crosslinked microspheres containing a biologically activeagent, in either gel or dispersion form, can be made in a single step.In addition to drug delivery applications, the method is suitable fornon-medical uses including delivery of agricultural materials such asherbicides and pesticides and in water treatment.

[0092] The present invention will be further understood by reference tothe following non-limiting examples.

EXAMPLE 1

[0093] Synthesis and Thermal Responsiveness of F127-(Lactate)6Acrylate.

[0094] a) Synthesis.

[0095] F127-(lactate)O-acrylate (unlactated control) (=F127A2?) wassynthesized by acrylatinglOO g of Pluronic™ F127 (polypropyleneoxide-polyethylene oxide block copolymer, BASF, mol. wt. 12000) (“F127”)in anhydrous toluene using triethylamine and acryloyl chloride, in anargon atmosphere at 60° C. for 10 minutes. The hot, turbid reactionmixture was filtered and the filtrate was added to a large excess ofhexane. The monomer was collected by vacuum filtration and dried invacuum to a constant weight.

[0096] Ft27-(lactate)6-acrylate was synthesized as follows. F127 wasmelt dried in vacuo at 100° C. for 4 hours. D,L-lactide (BoehringerIngelheim) was added to the melt under a nitrogen flush, followed bystannous octoate as a ring opening catalyst. After a reaction time of 4hours, the melt was dissolved in toluene and precipitated in a largeexcess of hexane. Acrylation of F127-(lactate)6 was carried out asdescribed above for the acrylation of F127-(lactate)O-acrylate. Allmacromonomers were characterized by NMR and HPLC.

[0097] The relationship between the macromer, the thermally-reversible(physical) gel, and the irreversible (crosslinked) gel is shown in FIG.1.

[0098] b) Measurement of the Sol-Gel Transition as a Function ofConcentration and Temperature.

[0099] Thermoreversible gel formation of the aqueous solutions of themacromonomers at a certain transition temperature was demonstrated. Thistransition temperature was recorded as a function of temperature andconcentration. The results demonstrated that sol-gel transition can becontrolled through the incorporation of hydrophobic lactyl units.

[0100] Transition temperature as a function of concentration wasdetermined by preparing 20% w/v aqueous solutions ofF127-(lactate)O-acrylate and F127-(lactate)6-acrylate as stocksolutions. 15 % (w/v), 12.5% (w/v), 10% (w/v) and 5% (w/v) macromonomeraqueous? solutions in screw cap vials were prepared by dilutions of thestock solutions. The solutions were allowed to equilibrate at 25° C. Thevials were inverted and observed for fluid flow. The concentration atwhich no fluid flow was observed was recorded (see Table 1).

[0101] The transition temperature as a fucntion of temperature wasdetermined by preparing 10% (w/v) aqueous solutions ofF127-(lactate)6-acrylate and F127-(lactate)O-acrylate and equilibratingthem at room temperature. (The concentration of the solutions are wt/vol% in aqueous solution unless otherwise stated.) The sample vials wereinmmersed in a temperature controlled bath and the fluid flow wasobserved at different temperatures. The temperature at which no fluidflow was observed was recorded (see Table 1). TABLE 1 Sol-Gel Sol-GelTransition Transition Macromonomers (% w/v)** (° C.)*** F127-(Lactate)0-30 40 Acrylate F127-(Lactate)6- 10 25 Acrylate

[0102] c) Polymerization and Measurement of Hydrogel Dimensions.

[0103] A 10% solution of F127-(lactate)6-acrylate in PBS (phosphatebuffered saline) was polymerized using long wave UV light. Thepolymerizations were performed in a cylindrical plastic mold. Darocur™2959 (Ciba Geigy) was used as the photoinitiator. The hydrogel wasallowed to reach equilibrium swelling by immersing in PBS for 24 hoursat ambient temperature. The change in dimension of the hydrogel attemperatures ranging from 0-50° C. was measured using vernier calipers,and is shown in FIG. 2. At low temperatures, the hydrophobic PPO(polypropylene oxide) segments of the hydrogel may dissolve and swell,and increase the dimensions of the gel. At high temperatures, the PPOsegments may become hydrophobic and collapse into micromicellarhydrophobic domains, which exclude water resulting in reduced swellingand smaller dimensions.

[0104] d) Degradation Experiments.

[0105] Hydrogels were prepared using 10% macromonomer solution asmentioned before and the degradation of hydrogel was monitoredgravimetrically at various intervals of time. The experiments wereperformed at 37° C. in PBS. The lactate based photopolymerized hydrogelcompletely degraded in 22 days (at 37° C., in PBS).

[0106] Thus, the macromers can be photopolymerized to formthermoresponsive hydrogels which degrade under physiological conditions.

[0107] The macromers and related prior art materials are referred toherein in the form XXXLLAA, where XXX is either part of the trade nameof a precursor polymer (e.g., L81 for Pluronic™ L81 poloxamer) or refersto another property of the base polymer (e.g., 8K for 8,000 nominalDalton PEO). LL denotes the terminal block, typically of a degradablehydroxy acid (e.g., L5 denotes an average of 5 lactate residues per armof the polymer), where L, G, C and TMC or T represent, respectively,lactate, glycolate, epsilon-caproate, and trimethylenecarbonate. AArepresents a terminal group; for example, A is for acrylate, so A2 wouldrepresent 2 acrylate terminations on the macromer as a whole.

EXAMPLE 2

[0108] Dextran Release by F127A2.

[0109] The non-degradable material, F127A2, was made as described abovein Example 1, with no addition of hydroxy acid to the Pluronic™ polymerbackbone. Dextran (labeled with fluorescein) of molecular weight 71,000daltons was mixed at 1% final concentration with F127A2 macromer (finalconcentration 10% wtlvol, in water) and polymerized as described inExample 1. Release of dextran was determined by visible absorbance.Release kinetics were significantly altered by temperature, as shown inFIG. 3.

EXAMPLE 3

[0110] Synthesis of Macromers with Biodegradable Linking Groups.

[0111] Four monomer types were made by the general procedures describedin Example 1, each containing about 4 units of each of four differentbiodegradable linkers, designated by L (lactate), C (caprolactone), G(glycolide), and TMC (trimethylene carbonate). Parameters for thesynthesis of the thermnosensitive macromonomers are listed in Table 2.Properties of the monomers characterized are listed in Table 3,including biodegradable segment and end group incorporation by HPLC andNMR, and Mn determined by GPC and NMR. TABLE 2 Feed Ratio Temp M.W. PPOPEO Monomer/ ° C./ Yield Compound (g/mole) M.W. M.W. diol time (h) (g)F127L4A2 12600 3780 8820 4 180-190/5 80.46 F127C4A2 12600 3780 8820 4180-190/5 81.38 F127G4A2 12600 3780 8820 4 180-190/5 71.89 F127TMC4A212600 3780 8820 4 180-190/5 79.29

[0112] TABLE 3 Biodeg. Biodeg. End End Seg. Seg. Group Group Mn Mn MnIncorp. Incorp. Incorp. Incorp. GPC NMR Expected Macromonomer (HPLC)(MNR) (HPLC) (NMR) g/mol g/mol g/mol F127L4A2 5.68 ± 0.01 5.58 2.09 ±0.01 2.00 10800 11316 12998 F127G4A2 5.39 ± 0.02 5.04 2.05 ± 0.02 2.3110800 10804 12942 F127C4A2 5.49 ± 0.02 5.45 2.09 ± 0.03 2.11 10000 1306213166 F127TMC4A2 — 3.26 2.08 ± 0.03 2.09 12100 NA —

[0113] The monomers differed in their rate of polymerization and rate ofdegradation. The long UV photopolymerization profiles are shown in FIG.4. The in vitro degradation profiles of the crosslinked hydrogels areshown in FIG. 5.

[0114] The macromers had similar biocompatibility profiles, as shown inFIG. 6, as measured by the HFF cell adhesion test. In FIG. 7, releaserates of fluorescent dextran at 37° C. and 0° C. is shown for a priorart material (F127A2) and for macromers with degradable hydrophobicblocks formed of lactide (F1271AA2), glycolide (F127G4A2) andcaprolactone (F127C4A2). A longer period of quasi-zero order delivery,after the initial burst, and a distinct difference in the rates ofefflux between the lower and higher temperatures, is obtained with themacromers including the degradable blocks, in comparison to the priorart material. In FIG. 8, the transition temperatures (for volume changeand change of dextran release rate) are shown as a function of macromerconcentration in the gel for the above materials and also a trimethylenecarbonate based material (F127TMC4A2), a “reverse” meroxapol materialwith lactide (25R8LAA2), and a “normal” material (F68MAA2) of equivalenthydrophobicity

[0115] The HFF test was conducted as follows:

[0116] a.) Preparation of Gel.

[0117] 0.5 gram of test material was dissolved in 4-5 ml standardreconstitution solution (Irgacure 1200 ppm, 3% Pluronic F127). Thesolution was filter sterilized using 0.2 micron filter. In a sterilehood, a glass coverslip (18 mm sq) was sterilized using 70% ethanol andwas placed in a 6 well, 35 mm tissue culture dish. 200 μL of the sterilemacromonomer solution was spread on a sterile coverslip. The solutionwas then exposed to long wavelength UV light (Black Ray, 20 mW/cm2, 1minute) to form a gel.

[0118] c) Preparation of Cell Suspension.

[0119] Human foreskin fibroblasts (HFF) cells were purchased from ATCC.Cells were used at a passage 22-23. HFF cells were cultured in astandard tissue culture ware in a humidified atmosphere containing 5%CO₂. Cells were detached from the culture flask using a 3 mltrypsin/EDTA solution (0.05%/0.53 mm) and centrifuged (2500 rpm, 3minutes). The cell pilot was resuspended in cell culture medium(DMEM+10% FCS) at a concentration of 250000 cells/ml.

[0120] d) Cell Attachment Assay.

[0121] The gels were washed with 3 ml DMEM (Dulbecco's Modified Eagles'Medium) solution and then seeded with 25000 cells/cm2 cell density.After 18 h, the gel surface and tissue culture polystyrene surface wereobserved under microscope and photographed. The gels were separated fromcoverslip and transferred into a new petri dish. The cells adhered tothe gels were detached using 3 ml trypsin/EDTA (0.05%/0.53 mm) solution.A Coulter counter was used to determine the cell density.

EXAMPLE 4

[0122] Effects of Linking Group Hydrophobicity on Small MoleculeDelivery.

[0123] Micelle-forming biodegradable macromers were synthesized andcharacterized which included a non-thermosensitive core. The macromersillustrated the effects of hydrophobicity on delivery capacity for smallhydrophobic molecules. The macromers were formed by synthesizingcopolymers of PEG (molecular weight 8000) with different combinations ofpolycaprolactone and polyglycolate which were then end capped withacrylate moieties. The structures are shown in FIG. 9, where p is thenumber of glycolic acid groups and q is the number of caprolactonegroups. Hydrophobicity of the mixed hydroxy acid blocks increases from Ato D. The ability of these monomers to solubilize model hydrophobicdrugs was demonstrated by a study of the CMC through the gradualdissolution of a molecular probe, 1,6 diphenyl 1,3,5-hexatriene (DPH).effect of hydrophobicity on drug incorporation into gels

[0124] a) Synthesis of Monomers.

[0125] The molecular structures of the monomers are shown in FIG. 9.Polyethylene glycol 8000 (Union Carbide) was melt-dried at 100-110° C.in vacuum (10-15 mm Hg) for 4-6 hours. Caprolactone (predistilled,Aldrich), and glycolide, were charged at appropriate ratios into aSchlenk-type reaction vessel and stannous 2-ethyl hexanoate (Sigma) wasadded as a ring opening catalyst. The reaction was carried out for 4hours in an inert atmosphere at 180° C. The reaction mixture was thencooled to 80° C., dissolved in toluene, precipitated in hexane and theproduct was collected by vacuum filtration. The product was redissolvedin toluene and dried by azeotropic distillation.

[0126] Acrylation was carried out by the dropwise addition of a 2 molarexcess of acryloyl chloride and triethylamine under a nitrogen flush at65° C. for 1 hour. By-product salts were removed by vacuum filtration.The product was isolated by precipitation in a large excess of hexanefollowed by vacuum filtration. The monomers were characterized by NMR ona Varian 300 MHz nuclear magnetic spectrometer.

[0127] b) Determination of Critical Micellar Concentrations.

[0128] The hydrophobic dye 1,6, diphenyl 1,3,5-hexatriene (Aldrich),(DPH), which demonstrates enhanced absorbance (356 mn) at the CMC due toassociative interactions, was used in this study. Alexandridis et al.,Macromolecules, 27:2414 (1994). A stock solution of DPH was prepared inmethanol (0.4 mM). Aqueous monomer solutions were prepared bydissolution in PBS and dilution to the desired concentrations. 10 μl ofthe dye solution were added to each vial with equilibration for at least1 hour. The absorption spectra of the polymer/dye/water solutions wererecorded in the 250-500 nm range using a Hitachi UV-VIS Spectrometer.

[0129] c) Photopolymerization.

[0130] Photopolymerization of the polymer solutions were carried out inboth visible and ultraviolet light systems as described in: Sawhney A.S. et al., Macromolecules, 26: 581 (1993); and PCT WO 93/17669 byHubbell J. A. et al.

[0131] d) In vitro Degradation.

[0132] 200 μl of 10% monomer solution were UV polymerized to form a gel.The degradation of the hydrogels was monitored at 37° C. in PBS.

[0133] e) Results

[0134] In the synthesis, hydrophobic segments of the monomers werechanged by using various combinations of caproate and glycolate linkagesin the molecule. The critical micellization point was obtained from thefirst inflection of the absorption vs. concentration curve. The curvesare shown in FIG. 10. It is evident from the curves that the solubilityof the dye is enhanced with increasing concentration of the monomer. TheCMC values during aggregation and photopolymerization for variousmonomers are listed in Table 4. TABLE 4 Critical Gel* Time Gel** TimeTotal Micellar Initiated Initiated Using Degradation Concentration UsingUV Visible Light time Monomer (%) Light (secs) (secs) (days) A 0.92 5.5± 0.4 8.9 ± 0.1 10 B 0.55 5.8 ± 0.1 8.2 ± 0.5 14 C 0.32 5.2 ± 0.2 9.8 ±0.4 16 D 0.28 4.6 ± 0.1 10.4 ± 0.3  44

[0135] The CMC value is lowered with increase in caproate content of themonomer. This may be due to the tighter aggregation of the hydrophobiccaproate moieties. The fast gelling ability of these monomers under UVand visible light is illustrated in Table 4. The gel times range between4-12 seconds. The photopolymerized hydrogels degrade under aqueousconditions. The degradation times, i.e., times to substantially completedissolution, varied from 10-44 days, increasing with cap/gly ratio. Thefast gelation times of these monomers, their ability to dissolvehydrophobic solutes and their controlled degradation rates render themexcellent candidates for localized drug delivery.

EXAMPLE 5

[0136] Synthesis of Macromers Forming Liquid Crystal Phases.

[0137] a) Synthesis of Macromers.

[0138] P1051AA2, P84L5A2 and T904LSA2 macromers were synthesized bystandard procedures, generally as described in Example 1, fromcommercial base polymers (P105 Pluronic™ poloxamer; T904 Tetronicfour-armed ionic-group containing polaxamer; P84 Pluronic™ reversepoloxamer, or meroxapol).

[0139] b) Characterization of Optical Effects and Drug ReleaseProperties.

[0140] Aqueous solutions were prepared, and observed for anomalousoptical effects (“Schlieren”) without crosslinking. Rates of release ofa drug were observed, wherein the drug had a molecular weight about 500D, and substantial water solubility, as well as a hydrophobic region.

[0141] Aqueous solutions of all three macromers formed “Schlieren” typeliquid crystalline phases at concentrations of 55% and higher, at roomtemperatures. A temperature study of the LC phases showed that the LCphases for P84LAA2 and T904LAA2 are not stable at temperatures higherthan 30-35° C. The LC phase for these two polymers phase separates intotwo phases at T>35° C., one being an isotropic polymeric phase that isnot transparent to light and another phase that seemed to consist ofwater. In contrast, a concentrated solution of P105LAA2 (75%w/v)displays a highly anisotropic LC phase that maintains its stability totemperatures up to 110° C.

[0142] Aqueous solutions of PIO105A2 (in high concentrations) formned ahighly anisotropic liquid crystalline phase (LC phase) that results ingood drug entrapment to slow down release It was also observed thatP84L5A2 and T904L5A2 had significant differences in the self-assemblingcharacteristics (LC). It is possible that the drug is entrapped in thestable, highly oriented LC Phase of a p10SL4A2/water system. P841L4A2and T904L4A2 form LC phases with water, but these phases are not stableabove 30-35° C. At higher temperatures, the drug as well as some of thewater are excluded from the polymeric domains.

EXAMPLE 6

[0143] Treatment of Burns.

[0144] The pluronic poloxamer based macromonomers, such as F127-TMCacrylate, have a “paste-like” consistency at temperatures above 37° C.,and have flow characteristics at low temperatures. A “cool” formulatedsolution, optionally containing an appropriate drug (such as anantibiotic) is poured on a burn site, providing instant relief. At bodytemperatures, the formulation gels to a paste like consistency. The gelis then crosslinked, preferably by the action of light on an includedphotoinitiator. The characterization of photopolymerized hydrogels ascarriers for therapeutic materials to influence wound healing isdescribed in Sawhney et al., “The 21st Annual Meeting of the Society forBiomaterials,” Mar. 18-22, 1995, San Francisco, Calif., Abstract, thedisclosure of which is incorporated herein by reference.

[0145] The hydrogel layer on the skin provides transdermal delivery ofdrug to the burn site; maintains high moisture levels on severely burnedsites, thus preventing dehydration; adheres strongly to the damagedtissue, and is elastic, thus preventing delamination and “peeling” ofthe hydrogel dressing; and absorbs exudate from the wound. After asuitable time, controlled by the nature of the lining group(trimethylene carbonate in this example, giving a residence time of overa week), the gel will dissolve into components which are absorbable orinnocuous. It has been demonstrated in other experiments that relatedgel formulations, based on a polyethyleneglycol backbone such as thematerial 8KL5A2 (i.e,. PEO of molecular weight 8,000, with 5 lactategroups on each end terminated with acrylate groups), do not retard thehealing of full thickness biopsy wounds in rat skin. The pentablockpolymer F127-TMC acrylate of Example 3 is improved in comparison to theprior-art 8KL5A2 polyethylene glycol-based triblock formula in that itgels spontaneously on the burn site, and thus does not tend to run offthe site before it can be photocrosslinked.

EXAMPLE 7

[0146] Use of Hydrophobic Macromers to Increase Tissue Adherence.

[0147] Use of macromers carrying one or more hydrophobic groups canimprove the adherence of a hydrogel to a biological material. A macromerhaving having this property was synthesised. The base polymer was aTetronic™ 4-armed polymer based on ethylene diamine, where each arm is aPEG—PPO—PEG triblock copolymer. The base polymer was extended withlactide as previously described in Example 1, and then capped with abouttwo moles of palmitoyl chloride per mole of polymer, in order to capabout half of the arms. The remainder of the hydroxyls were capped withacroyl chloride, as described in Example 1. The resulting macromer wasdispersed in water and was polymerized in contact with tissue, to whichit adhered tenaciously.

EXAMPLE 8

[0148] Formation of Microspheres

[0149] Pluronic™ based biodegradable macromers made as described aboveabove, such as the materials of Example 3, in an aqueous solution formedmicelles with a CMC value ranging from about 1% to 5 % w/v. Afterphotopolymerization, the structure of the micelle is substantiallypreserved.

EXAMPLE 9

[0150] Synthesis of F127-Dimer Isocyanate-F127 Lactate Acrylate

[0151] Two molecules of a macromer diol (Pluronic F127) are coupled withone molecule of a dilsocyanate (dimer isocyanate) to produce higher di-and tri-functional alcohols, to provide macromers with high elasticity,high distensibility and high tissue adherence.

[0152] The following reagents are used: Pluronic F127 (BASF lot # WPM N581B, Mn=12200); dimer isocyanate (DDI-1410, Henkel Lot# HL 20037, %NCO=14.1%); and dibutyltin dilaurate.

[0153] Synthesis of F127-DDI-F127: 366 g of Pluronic F127 was heated to100° C. under vacuum for four hours to produce a melt. DDI-1410 (8.94 g)and dibutyltin dilaurate (0.115 g) was added to the melt (melttemperature 70° C.) and stirred vigorously for 4 hours. The mixturereadily crystallized when cooled. Product was a white waxy crystallinematerial. Theoretical molecular weight=24,996 Daltons.

[0154] Synthesis of F127-DDI-F127 Lactate, diol: 100 g of F127-DDI-F127was dried for 4 hours under vacuum at 100° C. 4.67 g of (D,L) Lactidewas charged to the reaction pot under an argon flush. Stannous 2-ethylhexanoate (0.5 mole percent) was added to the reaction. The melt wasvigorously stirred at 150° C. under argon for 4 hours. The product wasisolated by precipitation in hexane, followed by filtration. The productwas a white, crystalline, flaky material.

[0155] Synthesis of F127-DDI-F127 Lactate₅ acrylate: 100 g ofF127-DDI-F127 Lactates diol was charged into a 1000 ml three-neckedreaction vessel. 800 ml of toluene (Aldrich, 0.005% water content) wasadded to the flask. 50-75 ml of toluene was azeotroped off to ensuremoisture free reactants. 2.427 ml of predistilled triethylamine,followed by 2.165 ml of acryloyl chloride was added to the reactionmixture at 65° C. After one hour of reaction time, the turbid reactionmixture was filtered, and isolated into a white powder by precipitationinto a large excess of hexane. The product was collected by vacuumfiltration and dried to a constant weight.

[0156] Molecular structure determination was carried out by NMR, IR. Theproduct was found to be soluble in water and crosslinkable by visibleand UV light. Percent water uptake of fully cured 10% w/w hydrogels=22.1%. Hydrogels formed by photopolymerization at 10% concentration whileon dead bovine tissue were determined to be generally well adherent.

[0157] P105-DDI-P105 lactate acrylate and L81-DDI-L81 lactate acrylatewas synthesized from the respective Pluronic poloxamer startingmaterials (P105,L81) by the procedure described above. These macromerswere insoluble in water. They were used to encapsulate bioactivemolecules in hydrophobic matrices to achieve sustained drug release.

EXAMPLE 10

[0158] Synthesis of F127-DDI-F127 Isophorone Isocyanate

[0159] The synthesis and polymerization of a macromer which crosslinkswithout involving free radical polymerization is demonstrated. 50 g ofF127-DDI-F127 diol, prepared as in Example 9, was dissolved in 100 ml oftoluene in a three necked reaction flask. 90 ml of toluene was distilledoff azeotropically at 110° C. under argon. The flask was maintained at100° C. for 12 hours under vacuum (12 mm Hg). The reaction flask wasthen cooled to room temp, and 200 ml of dry methylene chloride was addedto the reaction flask. 0.445 g of isophorone isocyanate (Aldrich) wasadded (in a bolus) to the reaction flask at approximately 30° C. 0.15 gof dibutyltin laurate was added to the reaction mixture. The reactionmixture was stirred under argon at 30° C. for 12 hours, and precipitatedin 1000 ml of hexane (EM Sciences). White flakes were collected byvacuum filtration, and rinsed with 150 ml of hexane. The product wasdried in a vacuum oven to a constant weight. Characterization by NMR, IRshowed synthesis of the expected material.

[0160] The polymerizability of F127-DDI-F127 isophorone isocyanate wasevaluated. Partially dried product (0.16 g) was added to 1.44 g ofdeionized water. The product initially formed bubbles in contact withwater, then dissolved over approximately 3 days to form a viscoussolution. To test polymerizability, 200 mg of F127-DDI-F127 isophoroneisocyanate solution of polyethyleneimine in methylene chloride. Thesolution was stirred vigorously for a few seconds. A gelatineous productwas observed. Gel time: 5.9 seconds. Polyethyleneimine is believed tohave hemostatic properties; this formulation thus is potentiallysuitable for a topical wound dressing. In addition, structures formed ofthese materials can be used as drug depots.

EXAMPLE 11

[0161] Effect of Hydrophobicity on Drug Release Kinetics for BulkDevices.

[0162] Macromers were synthesized having a wide range ofhydrophobicities ranging from 0-90% PPO content. All macromers weretested at 15% macromer concentration except those whose PPO content wasgreater than 60% which were used neat. FIG. 13 shows the rate of releaseof a small drug from gels of these macromers. At 10 and 15% macromerloading (8KL10, prior art; 25R81AA2, based on a “reverse” Pluronicpolymer) and PPO content of less than 60% hydrophobic partitioning didnot show a significant effect on prolonging 500 Da sparingly solubledrug release. Devices prepared with neat macromers (PPO content>60%; P84MA2 and L81L-A2, synthesized by general procedures as described above)showed a significant ability of these highly hydrophobic, densemacromers to retard water permeation and drug dissolution In the extremecase (L81L5A2; PPO content=90%), the release kinetics showed first orderrelease with half of the drug being released from the device over 17days with the remainder being eluted from the device over a total of 66days.

EXAMPLE 12

[0163] Effect of Polymer Hydrophobicity on Drug Diffusivity

[0164] Membranes of constant thickness were prepared from neat macromersof Example 11, and used as the diffusion barrier in a two-compartmentdialysis cell. FIGS. 14 and 15 show the increase in the concentration of500 Da drug in the receptor side of the cell over time. The diffusioncoefficient calculation was based on the following relationship:

D=J/(A*(ΔC/Δx)

[0165] where D is the diffusion coefficient, J is the measured flux, Ais the exposed area of the film, ΔC is the concentration gradient acrossthe film and Δx is the average film thickness. The diffusioncoefficients for macromers having 50% (P105L5A2) or 90% (L81L5A2)relative hydrophobic domain and were calculated to 1.6×10⁻⁹cm²/sec and5.63×10⁻¹⁰cm²/sec, respectively. Thus, diffusion was faster in the morehydrophobic material, as expected for a drug of low water solubility.

EXAMPLE 13

[0166] Release of Tetracycline and Taxol.

[0167] A 30% w/w solution of F127 trimethylene carbonate acrylate (asdescribed in Example 3) in phosphate buffered saline, pH7.4 was prepared3000 ppm Darocur® (Ciba Geigy) was incorporated in the solutions asphotoinitiator. Tetracycline (free base, crystalline, F. W. 444.44) wasincorporated in the macromer solution by equilibration for 12 hours at37 degrees C. Then, 200 microliters of the solution was crosslinked byUV light (10 W/cm2, full cure). In vitro release of tetracycline fromthe 200 microliter cured gel, after a brief rinse, was carried out in 5mls PBS, pH 7.4, 37° C. The PBS was exchanged daily to ensure “sink”conditions. The release profile is seen FIG. 16. After an initial burst,tetracycline was released steadily for nearly a week.

[0168] Taxol was incorporated into gels by similar procedures, exceptthat Tween™ surfactant was used to solubilize the Taxol concentrate. Asimilar release pattern to that seen with tetracycline was observed.

EXAMPLE 14

[0169] Urethane-Containing Macromers.

[0170] PEO of molecular weight 1450 was reacted with approximately Imole of lactide per end, using procedures described above, to give1.4KL2. The 1.4KL2 was weighed into a 100 ml flask (8.65 g) and 270 mlof dried toluene was added About 50 ml of toluene was distilled off toremove residual water as the azeotrope, and the solution was cooled.Then 0.858 g (825 microliter) of commercial 1,6 hexane-diisocyanate wasadded, and also 1 drop of dibutyltindilaurate (ca. 0.02 g). The solutionwas at 60 degrees at addition, and warmed to 70 degrees over about 10minutes. Heat was applied to maintain the solution at about 75 degreesfor about 3.5 hours NMR and IR spectra confirmed consumption of thediisocyanate, and the resulting solution was therefore expected tocontain alternating PEO and hexane blocks, linked by urethane linkages,and terminated by hydroxyls. This material can be capped with reactiveend groups, optionally after further extension with hydroxy acids, toform a reactive macromer. The urethane links and hexane blocks arepresent to promote tissue adherence.

[0171] Modifications and variations of the present invention will beobvious to those skilled in the art from the foregoing detaileddescription. Such modifications and variations are intended to comewithin the scope of the following claims.

What is claimed is:
 1. A macromer which is capable of forming a gel, themacromer comprising at least four covalently linked polymeric blocks,wherein a) at least one block is hydrophilic b) each hydrophilic blockindividually has a water solubility of at least 1 gram/liter; and c) atleast two blocks are sufficiently hydrophobic to aggregate to formmicelles in an aqueous continuous phase; wherein the macromer furthercomprises at least one crosslinkable group.
 2. The macromer of claim 1wherein the crosslinkable groups are separated by at least onedegradable linkage capable of degrading under physiological conditions.3. The macromer of claims 1 wherein at least one hydrophobic block isseparated from any crosslinkable group by at least one hydrophilicblock.
 4. The macromer of any of claim 1 comprising five total blocks.5. The macromer of claim 1 comprising at least two chemically distincthydrophobic blocks.
 6. A solution of a macromer of claim 1, furthercomprising a biologically active material.
 7. The macromer of claim 1wherein the macromer comprises at least one thermally sensitive region,and wherein a solution of the macromer is capable of gelling orcrosslinking to produce a hydrogel with a temperature dependent volume.8. The macromer of claim 7 wherein the rate of release of a drugincorporated in the hydrogel is dependent upon the volume of thehydrogel.
 9. The macromer of claim 1 wherein the macromer is capable ofthermoreversible gelation in an aqueous solution of the macromer at aconcentration of at least 2% by weight, and wherein the gelationtemperature is between about 0° C. and about 65° C.
 10. The macromer ofclaim 1 wherein the macromer has an optically anisotropic phase at aconcentration at or below the maximal solubility of the macromer in anaqueous solution, at a temperature between about 0 and 65° C.
 11. Themacromer of claim 1, further comprising at least one ionically chargedmoiety covalently attached to the macromer.
 12. The macromer of claim 1wherein the macromer has a phase transition temperature in the range of0 to 100° C., and wherein the transition temperature is affected by aproperty selected from the group consisting of the ionic composition ofan aqueous solution of the macromer and the concentration of macromer inthe aqueous solution.
 13. A mixture comprising the macromer of claim 1and a hydrophobic material non-covalently associated with the macromer.14. The mixture of claim 13, wherein the hydrophobic material isselected from the group consisting of a hydrocarbon, a lipid, a fattyacid, and a sterol.
 15. The macromer of claim 1 wherein thecrosslinkable group is selected from the group consisting of anethylenically unsaturated group, an epoxide, an isocyanate, anisothiocyanate, an aldehyde, an amine, a sulfonic acid and a carboxylicacid.
 16. The macromer of claim 1 wherein the hydrophobic blocks are thesame or different and are selected from the group consisting ofpolypropylene oxide, polybutylene oxide, hydrophobic mixed poly(alkyleneoxides), and oligomers of hydroxy acids, lactones, amino acids,anhydrides, orthoesters, phosphazenes, and phosphates.
 17. The macromerof claim 1 wherein the hydrophilic blocks are the same or different andare selected from the group consisting of poly(ethylene glycol),poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone),poly(ethyloxazoline), polysaccharides and amino acid polymers.
 18. Themacromer of claim 2 wherein the degradable linkage groups are the sameor different and are selected from the group consisting ofpoly(alpha-hydroxy acids), poly(amino acids), poly(anhydrides),poly(orthoesters), poly(phosphazines), poly(phosphoesters), andpolylactones.
 19. The macromer of claim 1 wherein at least twohydrophobic blocks are separated by a hydrophilic block.
 20. Themacromer of claim 1 wherein each hydrophobic block is separated by ahydrophilic block from any other hydrophobic block.
 21. The macromer ofclaim 1 wherein the dry macromer absorbs at least about 10% in weight ofwater.
 22. The macromer of claim 1 wherein the molecular weight of themacromer is at least 1000 Daltons.
 23. The macromer of claim 1 whereinthe molecular weight of the macromer is at least 2000 Daltons.
 24. Themacromer of claim 1 wherein the molecular weight of the macromer is atleast 4000 Daltons.
 25. A gel formed from an aqueous solution of themacromer of claim 1 or mixtures thereof, wherein the crosslinkablegroups are covalently crosslinked.
 26. The gel of claim 25 furthercomprising a biologically active material.
 27. The gel of claim 26wherein the biologically active material is provided in a form selectedfrom the group consisting of particles, microparticles, pro-drugconjugates, or liposomes.
 28. The gel of claim 25 wherein the gelchanges in permeability in response to one or more effects selected fromthe group consisting of changes in temperature, pH, ionic strength, andionic composition.
 29. The gel of claim 25 wherein the gel is formed ona surface of biological tissue.
 30. The gel of claim 25 wherein the gelis formed on a surface of a medical device.
 31. The gel of claim 25wherein the gel is formed between opposed surfaces, tending thereby toadhere said surfaces.
 32. A method of treating a medical condition,comprising applying to tissue in vivo an aqueous solution of agel-forming macromer, comprising at least four covalently-linkedpolymeric blocks, wherein a) at least one blocks is hydrophilic; b) eachhydrophilic block individually has a water solubility of at least 1gram/liter; and c) at least two blocks are sufficiently hydrophobic toaggregate to form micelles in an aqueous continuous phase; and whereinthe macromer further comprises at least one crosslinkable group.
 33. Themethod of claim 32 wherein the aqueous solution comprises a solution orsuspension of a biologically active material.
 34. The method of claim 33wherein the medical condition is a burn or abrasion of the skin.
 35. Themethod of claim 33 wherein the medical condition is a tissue disturbedby a surgical intervention.
 36. The method of claim 35 wherein thesurgery is angioplasty.
 37. The method of claim 35 wherein the surgeryis conducted through the cannula of a trocar.
 38. A method forcontrolling the rate of delivery of a biologically active material,comprising mixing the active material with a solution of a gel-formingmacromer and covalently crosslinking said macromer to form a gel,wherein the macromer comprises at least four blocks and at least onecovalently crosslinkable group, and wherein at least two the blocks arehydrophobic, and at least two of the blocks are hydrophilic.
 39. Themethod of claim 38 wherein the crosslinked gel changes in permeabilityin response to an effect selected from the group consisting of a changein temperature, a change in ionic concentration, and a change in pH. 40.The method of claim 38 wherein at least one hydrophobic block aggregatesin aqueous solution to form a hydrophobic domain.
 41. The method ofclaim 40 wherein the hydrophobicity of said domain is controlled byselecting the hydrophobicity of the block.
 42. The method of claim 40wherein the hydrophobicity of said domain is controlled by addinghydrophobic materials to the gel-forming macromer solution.
 43. Themethod of claim 38 wherein the active material is in the form of amicroparticle.
 44. The method of claim 38 wherein the gel forms amicroparticle after crosslinking.
 45. The macromer of claim 1 furthercomprising at least two hydrophilic blocks.
 46. The macromer of claim 1provided in a pharmaceutically acceptable carrier.
 47. The macromer ofclaim 46 wherein the macromer is provided in a carrier suitable forparenteral administration.
 48. The method of claim 32 wherein themacromer further comprises at least two hydrophilic blocks.
 49. Themethod of claim 32 wherein the macromer is applied to tissue in apharmaceutically acceptable carrier.
 50. The method of claim 49 whereinthe macromer is provided in a pharmaceutically acceptable carrier forparenteral administration.